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1.
Artigo em Inglês | MEDLINE | ID: mdl-29782958

RESUMO

A deficiency of maternal folic acid (FA) can compromise the function and development of the brain, and may produce a susceptibility to diseases such as schizophrenia (SZ) in the later life of offspring. The aim of this study was to evaluate the effects of both FA deficient and FA supplemented diets during gestation and lactation on behavioural parameters, the markers of oxidative stress and neurotrophic factors in adult offspring which had been subjected to an animal model of SZ. Female mother rats (Dam's) were separated into experimental maternal groups, which began receiving a special diet (food) consisting of the AIN-93 diet, a control diet, or an FA deficient diet during the periods of pregnancy and lactation. Dam's receiving the control diet were further subdivided into four groups: one group received only control diet, while three groups to receive supplementation with FA at different doses (5, 10 and 50 mg/kg). Adult offspring bred from the Dam's were divided into ten groups for induction of the animal model of SZ through the administration of ketamine (Ket) (25 mg/kg). After the last administration of the drug, the animals were subjected to the behavioural tests and were then euthanized. The frontal cortex (FC) and hippocampus (Hip) were then dissected for later biochemical analysis. Our data demonstrates that Ket induced the model of SZ by altering the behavioural parameters (e.g. hyperlocomotion, social impairment, deficits in the sensory-motor profile and memory damage in the adult animals); and also caused changes in the parameters of oxidative stress (lipid hydroperoxide - LPO; 8-isoprostane - 8-ISO; 4-hydroxynonenal - 4-HNE; protein carbonyl content; superoxide dismutase - SOD and catalase - CAT) as well as in the levels of neurotrophic factors (brain-derived neurotrophic factor - BDNF and nerve growth factor - NGF) particularly within the FC of adult offspring. A deficiency in maternal FA, alone or in combination with ket, was able to induce hyperlocomotion and social impairment in the offspring with increased levels of lipid and protein damage (LPO, 8-ISO, 4-HNE, carbonylation of protein) within the FC, increased activity of antioxidant enzymes (SOD and CAT) in both of the brain structures studied, and also reduced the levels of neurotrophins (BDNF and NGF), particularly within the Hip of the adult offspring. Supplementation of FA (5, 10 and 50 mg/kg) to the Dam's was mostly able to prevent the cognitive damage which was induced by Ket in the adult animals. FA (10 and 50 mg/kg) attenuated the action of Ket in the animals in relation to the biochemical parameters, proving the possible neuroprotective effect of FA in the adulthood of offspring that were subjected to the animal model of SZ. Our study indicates that the intake of maternal FA during pregnancy and lactation plays an important role, particularly in the regulation of markers of oxidative stress and neurotrophins.


Assuntos
Comportamento Animal , Encéfalo/metabolismo , Fatores de Crescimento Neural/metabolismo , Estresse Oxidativo , Esquizofrenia/metabolismo , Animais , Comportamento Animal/fisiologia , Encéfalo/crescimento & desenvolvimento , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Ácido Fólico/administração & dosagem , Deficiência de Ácido Fólico , Ketamina , Masculino , Estresse Oxidativo/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Distribuição Aleatória , Ratos Wistar , Psicologia do Esquizofrênico
2.
Mol Neurobiol ; 55(3): 2301-2319, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28342013

RESUMO

Although folic acid (FA) supplementation is known to influence numerous physiological functions, especially during pregnancy, little is known about its direct effects on the mothers' health. However, this vitamin is essential for the health of the mother and for the normal growth and development of the fetus. Thus, the aim of this study was (1) to evaluate the cognitive effects and biochemical markers produced by the AIN-93 diet (control), the AIN-93 diet supplemented with different doses of FA (5, 10, and 50 mg/kg), and a FA-deficient diet during pregnancy and lactation in female mother rats (dams) and (2) to evaluate the effect of maternal diets on inflammatory parameters in the adult offspring which were subjected to an animal model of schizophrenia (SZ) induced by ketamine (Ket). Our study demonstrated through the Y-maze test that rats subjected to the FA-deficient diet showed significant deficits in spatial memory, while animals supplemented with FA (5 and 10 mg/kg) showed no deficit in spatial memory. Our results also suggest that the rats subjected to the FA-deficient diet had increased levels of carbonylated proteins in the frontal cortex and hippocampus and also increased plasma levels of homocysteine (Hcy). Folate was able to prevent cognitive impairments in the rats supplemented with FA (5 and 10 mg/kg), data which may be attributed to the antioxidant effect of the vitamin. Moreover, FA prevented protein damage and elevations in Hcy levels in the rats subjected to different doses of this vitamin (5, 10, and 50 mg/kg). We verified a significant increase of the anti-inflammatory cytokine (interleukin-4 (IL-4)) and a reduction in the plasma levels of proinflammatory cytokines (interleukin-6 (IL-6)) and TNF-α) in the dams that were subjected to the diets supplemented with FA (5, 10, and 50 mg/kg), showing the possible anti-inflammatory effects of FA during pregnancy and lactation. In general, we also found that in the adult offspring that were subjected to an animal model of SZ, FA had a protective effect in relation to the levels of IL-4, IL-6, and TNF-α, which indicates that the action of FA persisted in the adult offspring, since FA showed a lasting effect on the inflammatory response, which was similar in both the dams and their offspring. In conclusion, the importance of supplementation with FA during pregnancy and lactation should be emphasized, not only for the benefit of the offspring but also for the health of the mother. All this is due to the considerable protective effect of this vitamin against oxidative damage, cognitive impairment, hyperhomocysteinemia, immune function, and also its ability in preventing common processes in post-pregnancy stages, as well as in reducing the risks of neurodevelopmental disorders and enhancing fetal immune development.


Assuntos
Suplementos Nutricionais , Deficiência de Ácido Fólico/dietoterapia , Ácido Fólico/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal/dietoterapia , Esquizofrenia/dietoterapia , Complexo Vitamínico B/administração & dosagem , Animais , Modelos Animais de Doenças , Feminino , Deficiência de Ácido Fólico/induzido quimicamente , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Ketamina/toxicidade , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente , Esquizofrenia/metabolismo
3.
Neuroscience ; 259: 223-31, 2014 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-24316471

RESUMO

Supplementation with omega-3 has been identified as an adjunctive alternative for the treatment of psychiatric disorders, in order to minimize symptoms. Considering the lack of understanding concerning the pathophysiology of schizophrenia, the present study hypothesized that omega 3 prevents the onset of symptoms similar to schizophrenia in young Wistar rats submitted to ketamine treatment. Moreover, the role of oxidative stress in this model was assessed. Omega-3 (0.8g/kg) or vehicle was given by orogastric gavage once daily. Both treatments were performed during 21days, starting at the 30th day of life in young rats. After 14days of treatment with omega-3 or vehicle, a concomitant treatment with saline or ketamine (25mg/kg ip daily) was started and maintained until the last day of the experiment. We evaluated the pre-pulse inhibition of the startle reflex, activity of antioxidant systems and damage to proteins and lipids. Our results demonstrate that supplementation of omega-3 prevented: decreased inhibition of startle reflex, damage to lipids in the hippocampus and striatum and damage to proteins in the prefrontal cortex. Furthermore, these changes are associated with decreased GPx in brain tissues evaluated. Together, our results suggest the prophylactic role of omega-3 against the outcome of symptoms associated with schizophrenia.


Assuntos
Lesões Encefálicas/dietoterapia , Lesões Encefálicas/etiologia , Ácidos Graxos Ômega-3/administração & dosagem , Transtornos Mentais/prevenção & controle , Esquizofrenia/complicações , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glutationa Peroxidase/metabolismo , Ketamina/toxicidade , Masculino , Malondialdeído/metabolismo , Transtornos Mentais/etiologia , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente , Esquizofrenia/patologia , Filtro Sensorial/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
4.
Neuroscience ; 248: 252-60, 2013 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-23769892

RESUMO

Maternal deprivation has been associated with physiological and developmental changes that may be related to an increased risk for childhood and adult neuropsychiatric diseases. A growing number of studies demonstrated the importance of childhood experiences in the development of psychosis and schizophrenia in adulthood. Therefore, the present study investigated different behavior responses in rats following maternal deprivation and/or ketamine treatment in adulthood. Male rats were subjected to maternal deprivation for 180 min from postnatal day-01 to postnatal day-10. We evaluated locomotor activity, avoidance task and social interaction of adult male rats deprived or not deprived that were administered with saline or acute subanesthetic doses of ketamine (5, 15 and 25 mg/kg, i.p.). Our results show that only ketamine (25 mg/kg, i.p.) treatment in the adult rats lead to hyperlocomotion but not ketamine (5 and 15 mg/kg) and maternal deprivation alone. However, maternally deprived rats treated with ketamine (5 mg/kg) induced hyperlocomotion. Additionally, ketamine (25 mg/kg) and maternal deprivation alone induced cognitive deficit in the avoidance task. Rats deprived of and treated with ketamine (5, 15 and 25 mg/kg) also lead to memory deficit. Moreover, ketamine (25 mg/kg) and maternal deprivation alone increased latency to start social behavior. However, ketamine (5 mg/kg) and maternal deprivation lead to an increase of latency to start social behavior. Biochemistry data showed that all doses of ketamine and ketamine plus maternal deprivation increased the acetylcholinesterase (AChE) activity in the prefrontal cortex, hippocampus and striatum. The major doses of ketamine associated with maternal deprivation induced a major increase of AChE activity. Together, our results suggest that animals subjected to maternal deprivation had an increased risk for schizophrenia-like behavior and cholinergic alteration.


Assuntos
Acetilcolinesterase/metabolismo , Envelhecimento/psicologia , Comportamento Animal , Privação Materna , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Animais , Aprendizagem da Esquiva , Modelos Animais de Doenças , Ketamina/toxicidade , Locomoção , Masculino , Memória , Atividade Motora , Ratos , Esquizofrenia/induzido quimicamente , Comportamento Social
5.
Braz J Med Biol Res ; 34(10): 1265-9, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11593300

RESUMO

The effects of in vivo chronic treatment and in vitro addition of imipramine, a tricyclic antidepressant, or fluoxetine, a selective serotonin reuptake inhibitor, on the cortical membrane-bound Na+,K+-ATPase activity were studied. Adult Wistar rats received daily intraperitoneal injections of 10 mg/kg of imipramine or fluoxetine for 14 days. Twelve hours after the last injection rats were decapitated and synaptic plasma membranes (SPM) from cerebral cortex were prepared to determine Na+,K+-ATPase activity. There was a significant decrease (10%) in enzyme activity after imipramine but fluoxetine treatment caused a significant increase (27%) in Na+,K+-ATPase activity compared to control (P<0.05, ANOVA; N = 7 for each group). When assayed in vitro, the addition of both drugs to SPM of naive rats caused a dose-dependent decrease in enzyme activity, with the maximal inhibition (60-80%) occurring at 0.5 mM. We suggest that a) imipramine might decrease Na+,K+-ATPase activity by altering membrane fluidity, as previously proposed, and b) stimulation of this enzyme might contribute to the therapeutic efficacy of fluoxetine, since brain Na+,K+-ATPase activity is decreased in bipolar patients.


Assuntos
Antidepressivos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Fluoxetina/farmacologia , Imipramina/farmacologia , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos , Membranas Sinápticas/efeitos dos fármacos , Animais , Antidepressivos Tricíclicos/farmacologia , Córtex Cerebral/enzimologia , Ratos , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Membranas Sinápticas/enzimologia
6.
Braz. j. med. biol. res ; 34(10): 1265-1269, Oct. 2001. graf
Artigo em Inglês | LILACS | ID: lil-299841

RESUMO

The effects of in vivo chronic treatment and in vitro addition of imipramine, a tricyclic antidepressant, or fluoxetine, a selective serotonin reuptake inhibitor, on the cortical membrane-bound Na+,K+-ATPase activity were studied. Adult Wistar rats received daily intraperitoneal injections of 10 mg/kg of imipramine or fluoxetine for 14 days. Twelve hours after the last injection rats were decapitated and synaptic plasma membranes (SPM) from cerebral cortex were prepared to determine Na+,K+-ATPase activity. There was a significant decrease (10 percent) in enzyme activity after imipramine but fluoxetine treatment caused a significant increase (27 percent) in Na+,K+-ATPase activity compared to control (P<0.05, ANOVA; N = 7 for each group). When assayed in vitro, the addition of both drugs to SPM of naive rats caused a dose-dependent decrease in enzyme activity, with the maximal inhibition (60-80 percent) occurring at 0.5 mM. We suggest that a) imipramine might decrease Na+,K+-ATPase activity by altering membrane fluidity, as previously proposed, and b) stimulation of this enzyme might contribute to the therapeutic efficacy of fluoxetine, since brain Na+,K+-ATPase activity is decreased in bipolar patients


Assuntos
Animais , Ratos , Antidepressivos , Córtex Cerebral , Fluoxetina , Imipramina , ATPase Trocadora de Sódio-Potássio , Membranas Sinápticas , Antidepressivos Tricíclicos , Córtex Cerebral , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina , ATPase Trocadora de Sódio-Potássio , Membranas Sinápticas
7.
Neurochem Res ; 26(11): 1195-200, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11874200

RESUMO

The objective of the present study was to investigate the effects of preincubation of hippocampus homogenates in the presence of homocysteine or methionine on Na+, K+-ATPase and Mg2+-ATPase activities in synaptic membranes of rats. Homocysteine significantly inhibited Na+, K+-ATPase activity, whereas methionine had no effect. Mg2+-ATPase activity was not altered by the metabolites. We also evaluated the effect of incubating glutathione, cysteine, dithiothreitol, trolox, superoxide dismutase and GM1 ganglioside alone or incubation with homocysteine on Na+, K+-ATPase activity. Tested compounds did not alter Na+, K+-ATPase and Mg2+-ATPase activities, but except for trolox, prevented the inhibitory effect of homocysteine on Na+, K+-ATPase activity. These results suggest that inhibition of this enzyme activity by homocysteine is possibly mediated by free radicals and may contribute to the neurological dysfunction found in homocystinuric patients.


Assuntos
Encéfalo/enzimologia , Hipocampo/enzimologia , Homocisteína/farmacologia , Estresse Oxidativo/fisiologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Animais , Cromanos/farmacologia , Cinética , Metionina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/farmacologia
8.
Neuroreport ; 11(10): 2331-4, 2000 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-10923695

RESUMO

Buffered methylmalonate (MMA) was injected s.c. into rats twice a day at 8 h intervals from 5 to 25 days of age (chronic treatment), or into 10-day-old rats three times a day at 1 h intervals (acute treatment). Control rats received saline in the same volumes. Na+,K+-ATPase and Mg2+-ATPase activities were determined in the synaptic plasma membranes from cerebral cortex of rats. Na+,K+-ATPase activity was reduced by 30-40% in MMA-treated rats, whereas Mg2+-ATPase activity was not. In contrast, MMA at final concentrations ranging from 0.1 to 2.0 mM had no in vitro effect on these enzyme activities. However, when brain homogenates were incubated with 2 mM MMA before membrane preparation, Na+,K+-ATPase activity was decreased by 44%. Furthermore, this reduction was totally prevented by the simultaneous addition of glutathione and MMA, suggesting that oxidation of thiol groups or other oxidative damage to the enzyme could be responsible for this effect.


Assuntos
Envelhecimento/metabolismo , ATPase de Ca(2+) e Mg(2+)/metabolismo , Córtex Cerebral/enzimologia , Ácido Metilmalônico/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Membranas Sinápticas/enzimologia , Animais , Membrana Celular/enzimologia , Córtex Cerebral/crescimento & desenvolvimento , Glutationa/farmacologia , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos
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